Body fluid processor enabling direct hemoperfusion

ABSTRACT

A safe and practically useful body fluid processor whereby blood taken out from a patient can be directly processed, characterized by having a favorable passage of the blood cell and showing an extremely low risk of the generation and leakage of microparticles. Namely, a body fluid processor enabling direct hemoperfusion wherein the ratio of sedimented particles to the volume of the space in which the particles for processing body fluid are to be packed is 100% or less and the space in which the particles for processing body fluid are to be packed in the body fluid processor is filled with the particles for processing body fluid and a filling liquid at a ratio of 95% or more but not more than 100%.

TECHNICAL FIELD

The present invention relates to a body fluid processor enabling directprocessing of the blood in the extracorporeal circulation therapy wherethe blood taken out from a patient is processed to reduce theconcentrations of disease-related substances and then returned to thepatient and more particularly to a safe and practically useful bodyfluid processor having a favorable passage of the blood cell and showingan extremely low risk of leakage of microparticles.

BACKGROUND ART

In diseases resulting from accumulation of disease-related factors inblood, particularly in cases where the administration of drugs, forinstance, is not sufficiently successful, blood purification byextracorporeal circulation (extracorporeal circulation treatment) isused as an effective therapeutic approach. Extracorporeal circulationtreatment is a method of treatment which comprises taking out blood fromthe body, modifying it in some way or other to remove or ameliorate thedisease-related factors such as the causative substances accumulated inthe blood, abnormal cells, etc., and returning the blood so modified tothe patient.

In the conventional extracorporeal circulation treatment where targetsof removal are substances of low molecular weight, the removal byhemodialysis, hemofiltration or hemodialysis-filtration is efficient andhas been exploited successfully for removal of the waste substancesaccumulated in the blood of a patient with a disease of the kidney(renal failure), for instance. For those cases in which the targets ofremoval are substances having high molecular weights which cannot beremoved by hemodialysis or the like, many protocols have been developedand are in routine use for the blood purification by hemoperfusion whichcomprises separating plasma from blood with a plasma separating membraneor the like in advance and processing the plasma with a body fluidprocessor. For reducing the concentration of the causative substancepresent in plasma, several methods inclusive of adsorption, separationwith a membrane, and separation by precipitation are known.

As a specific system for extracoporeal circulation treatment in which anadsorbent is used to remove causative substances from plasma, there is asystem wherein the adsorbent is packed in a vessel equipped with aninlet and an outlet, the plasma is caused to flow directly into thevessel, and the plasma flowing out is returned to the patient (on-linesystem) or a system wherein the plasma is transferred to a blood bag orthe like filled with the adsorbent in advance and, after mixing, theplasma, recovered by filtering off the adsorbent, is returned to thepatient (batch system). From the standpoint of easy handling, theon-line system is used with preference.

Meanwhile, as an extracorporeal circulation treatment utilizing theparticles for processing body fluid, a system in which the plasma is notseparated from the blood but the blood is directly exposed to theparticles for processing body fluid is attracting attention of late forits easy handling. The on-line system in which the blood is directlyprocessed is called the direct hemoperfusion system. In this directhemoperfusion system, it is necessary that the blood cells may passthrough clearances between the particles for processing body fluid in astable manner and there should be substantially no leakage of foreignmatter, such as microparticles, from the body fluid processor. Inaddition, it must be insured that the blood can be efficiently processedto complete the treatment in a short time not imposing appreciableburdens on the patient and medical staff. However, this is technicallynot easily feasible.

One of the important factors enabling a stable direct hemoperfusion isthe diameter of the particles for processing body fluid. Generally theefficiency of body fluid processing can be improved by reducing the meanparticle diameter and increasing the effective surface area of theparticles for processing body fluid to be used but if the particlediameter is excessively decreased, the clearance between particles isdiminished to interfere with passage of the blood cells so that a stabledirect hemoperfurion becomes difficult.

Researches have heretofore been undertaken on the particles forprocessing body fluid suitable for direct hemoperfusion systems in theaspect of physical and chemical characteristics of the particles forprocessing body fluid. Japanese Kokai Publication Sho-63-115572, withattention directed to the mean particle diameter and particle sizedistribution, discloses that the particles so engineered that “thevolume mean particle diameter is 80 to 400 μm, that particles accountingfor not less than 80 volume % are distributed within ±20% of the volumemean particle diameter, and that the percentage of particles smallerthan 74 μm in diameter is not less than 5 volume % while that ofparticles smaller than 25 μm in diameter is not more than 0.1 volume %”,can be utilized as beads enabling direct hemoperfusion. Japanese KokaiPublication Hei-10-005329 describes that “when a sulfated polysaccharideand/or a salt thereof is coupled to a water-insoluble carrier”, theblood perfusion is improved and the mean particle diameter can bereduced as compared with the intact water-insoluble carrier.

For both of the above artifacts, their utility as the particles forprocessing body fluid has been studied but in order that these artifactsmay be practically useful, it is not only essential that the artifactsas such be satisfactory enough as the particles for processing bodyfluid but also necessary that body fluid processors prepared by packingthese artifacts display satisfactory characteristics.

The important point of any body fluid processor of the directhemoperfusion type from the standpoint of practical utility is that itshows a favorable passage of the blood cells and the blood can beallowed to flow through it at as high a speed as possible in a stablemanner. When these requirements are satisfied, an efficient therapy canbe administered in a short session time not imposing any appreciableburden on the patient and medical staff.

The important point of a body fluid processor of the directhemoperfusion type from safety viewpoints is a low risk of leakage ofmicroparticles from the body fluid processor. When a large amount ofmicroparticles exists in the body fluid processor, the microparticlestend to be carried away by blood from the body fluid processor and findtheir way into the patient's vascular system to clog the capillary bloodvessels. Therefore, if only for the purpose of minimizing the risk ofleakage of microparticles, it is ideal to provide a body fluid processorpacked with the particles for processing body fluid having no potentialof generation of microparticles in a microparticles-free condition.However, since porous particles are often used as the particles forprocessing body fluid in order that the body fluid processing may beaccomplished with efficiency, it is technically difficult to provide theparticles for processing body fluid which do not generate microparticlesand hence it is virtually impossible to implement such an ideal bodyfluid processor. Therefore, it is of great importance to pack theparticles for processing body fluid with the lowest possible potentialof generation of microparticles in as microparticles-free condition aspossible and in a manner protected against the generation ofmicroparticles within the body fluid processor even when the processoris subjected to vibrations.

As a means for solving above problems, a method of controllinggeneration of microparticles is known as disclosed in Japanese KokokuPublication Sho-61-11620 wherein the “adsorbent is pressed to securelyfix it in a column” so that the particles for processing body fluid maynot readily move within the body fluid processor. However, in the artdescribed in this patent literature, it is not discussed or exploredwhether the device is useful as a body fluid processor enabling directhemoperfusion, that is to say whether the blood can be directly passedthrough the device in a stable manner. In a body fluid processor of thedirect hemoperfusion type, if the particles for processing body fluidare immobilized by pressing, it is likely that the clearance betweenparticles is narrowed to interfere with the free flow of blood or theparticles are destroyed by compressive forces to generatemicroparticles.

Conversely when the particles for processing body fluid are not heldstationary but are free to move within the body fluid processor, it mayhappen that vibrations, for instance, cause collision of the particlesfor processing body fluid to generate microparticles.

Thus, no sufficient studies have heretofore been undertaken on the bodyfluid processor enabling direct hemoperfusion from safety and practicalutility points of view.

SUMMARY OF THE INVENTION

In the above state of the art, the present invention provides a bodyfluid processor of direct hemoperfusion type which shows an extremelylow risk of the generation and leakage of microparticles and permitsblood perfusion at as high a flow rate as practicable and in a stablemanner.

The inventors of the present invention did intensive studies on thecorrelation of the packed condition of the particles for processing bodyfluid and a filling liquid with the efficiency of blood perfusion andleakage of microparticles. As a consequence, they found that when theratio of sedimented particles to the volume of the space in which theparticles for processing body fluid are to be packed is 100% or less andthe space in which the particles for processing body fluid are to bepacked is filled with the particles for processing body fluid and afilling liquid at a ratio of 95% or more but not more than 100%, therecan be obtained a body fluid processor of practical utility which has afavorable passage of the blood cell even at a high flow rate and showsan extremely low risk of the generation and leakage of microparticles.The present invention has accordingly been developed.

The present invention, therefore, is directed to

a body fluid processor enabling direct hemoperfusion,

which comprises a vessel equipped with a fluid inlet, a fluid outlet anda mesh attached adjacent to said fluid outlet,

said vessel being packed with the particles for processing body fluidand a filling liquid,

the ratio of sedimented particles to the volume of the space in whichthe particles for processing body fluid are to be packed being 100% orless and

the space in which the particles for processing body fluid are to bepacked in the body fluid processor being filled with the particles forprocessing body fluid and a filling liquid at a ratio of 95% or more butnot more than 100%.

The present invention is further directed to

a body fluid processor enabling direct hemoperfusion,

wherein the mean particle diameter of the particles for processing bodyfluid is 80 μm through 500 μm;

a body fluid processor enabling direct hemoperfusion,

wherein the aperture size of the mesh is not less than 20 μm but lessthan ½ of the mean particle diameter of the particles for processingbody fluid;

a body fluid processor enabling direct hemoperfusion,

wherein the particles for processing body fluid are hard particles;

a body fluid processor enabling direct hemoperfusion,

wherein the carrier for the particles for processing body fluid is ahydrophilic carrier;

and a body fluid processor enabling direct hemoperfusion,

wherein the carrier for the particles for processing body fluid is acarrier made of a cellulosic material.

DETAILED DESCRIPTION OF THE INVENTION

The vessel of the body fluid processor for use in the invention isequipped with a fluid inlet, a fluid outlet, and a mesh attachedadjacent to said liquid outlet.

The constituent material of the vessel is not particularly restrictedbut may for example be polypropylene or polycarbonate.

The mesh to be used should be one that can be retained in position so asto preclude escape of the particles for processing body fluid from thebody fluid processor and capable of allowing blood perfusiontherethrough. The construction of the mesh may be any of an interlacedfilament structure, a woven fabric, a flat apertured plate having amultiplicity of through-holes, a nonwoven fabric, a filter such as acotton plug, and a bamboo blind-like structure, among others. Thematerial of such a mesh is not particularly restricted but may forexample be any of polyester, polyethylene, polypropylene, polyamide, andnylon.

While the through-holes of a mesh through which blood flows are referredto as apertures, it is to be understood that when the configuration ofthe aperture is circular, the diameter of the circle can be taken as theaperture size. In the case of a square configuration, the diameter of anequivalent circle of the same area can be used. When the aperture is abamboo blind-like, the length on the side of shorter interval can beused.

To allow blood to flow through, the aperture size of the mesh ispreferably not less than 20 μm. If it is less than this threshold, theblood cells are liable to be trapped by the meshes. However, in orderthat the leakage of the particles for processing body fluid may beprevented, the aperture size of the mesh is preferably less than ½ ofthe mean diameter of the particles for processing body fluid. The morepreferred aperture size is not less than 30 μm but less than ⅖ of themean diameter of the particles for processing body fluid. Particularlywhen there is a gradient in the particle size distribution, it isadvisable to take particles smaller than the mean diameter into accountand select an aperture size small enough to prevent leak-out of suchsmaller particles.

In addition, for preventing loss of the particles for processing bodyfluid from the body fluid processor through the fluid inlet, there maybe attached a similar mesh adjacent to the fluid inlet.

In the body fluid processor of the invention, the ratio of sedimentedparticles to the volume of the space in which said particles are to bepacked is 100% or less and the space in which the particles forprocessing body fluid are to be packed in the body fluid processor isfilled with the particles for processing body fluid and a filling liquidat a ratio of 95% or more but not more than 100%.

For the convenience of description, the ratio of sedimented particles tothe volume of the space in which the particles for processing body fluidare to be packed will hereinafter be referred to briefly as “packingratio” and the ratio of the particles for processing body fluid and afilling liquid to the volume of the space in which the particles forprocessing body fluid in the body fluid processor are to be packed willbe referred to briefly as “occupancy ratio”.

The packing ratio in the context of the invention can be calculated bymeans of the following equation:Packing ratio (%)=Va/Vj×100where Va represents the sedimentation volume of the particles forprocessing body fluid packed in the space in which the particles forprocessing body fluid are to be packed and Vj represents the volume ofthe space in which the particles for processing body fluid are to bepacked.

In this connection, Va is determined as follows. Thus, the whole amountof the particles for processing body fluid packed in the space in whichthe particles for processing body fluid are to be packed is transferred,in the form of a slurry prepared by addition of water, to a measuringcylinder and the particles for processing body fluid in slurry form areallowed to settle spontaneously in the measuring cylinder. Then, thismeasuring cylinder is placed on a base such as a rubber mat resistant tothe impact of a falling glassware and the measuring cylinder is droppedperpendicularly from a height of about 10 cm about 10 times. Afterallowing the cylinder to sit for not less than 15 minutes, thesedimentation volume of the particles for processing body fluid is readout and recorded. The above dropping and sitting procedure is repeatedand the sedimentation volume of the particles for processing body fluidin the stage where there is no change in the volume any longer isrecorded as Va.

The occupancy ratio in the present invention is calculated as follows.Thus, the whole amount of the particles for processing body fluid and afilling liquid packed in the space in which the particles for processingbody fluid are to be packed is transferred, in the form of a slurryprepared by addition of water (volume: Vw), to a measuring cylinder. Thevolume (Vin) of this whole slurry is found by reading the scale of thecylinder. The occupancy ratio is calculated by means of the followingequation.Occupancy ratio (%)=(Vin−Vw)/Vj×100

The state in which the occupancy ratio is 100% corresponds to the statein which the space to be packed with the particles for processing bodyfluid within the body fluid processor has been packed with the samevolume of the particles for processing body fluid as the volume of saidspace, with the result that the particles for processing body fluid willnot be easily displaced, nor will the particles for processing bodyfluid be deformed or compacted; thus it is an ideal state at low risk ofthe generation of microparticles due to vibrations, for instance.However, in the actual manufacturing of body fluid processors, it isimpossible to invariably align the packing ratio of the particles forprocessing body fluid at 100% and, therefore, a variation is inevitablein the packing ratio of body fluid processors manufactured.

On the other hand, when the packing ratio is less than 100%, theparticles for processing body fluid are not securely immobilized but arefree to move within the body fluid processor so that it may happen thatvibrations, for instance, cause collisions of the particles forprocessing body fluid and, hence, generation of microparticles. In otherto reduce the possibility of flow-out of microparticles from the bodyfluid processor in the course of treatment, it is preferable that thenumber of microparticles in the body fluid processor should be as low aspossible.

Under the circumstances, the inventors of the present invention didintensive studies and found that, when the packing ratio is not morethan 100% and the occupancy ratio is 95% through 100%, the resultingbody fluid processor enables direct hemoperfusion through which bloodmay flow in a practically acceptable manner while generation ofmicroparticles is suppressed.

When the packing ratio exceeds 100%, the particles for processing bodyfluid are held stationary in the body fluid processor and cannot easilymove so that it is not likely that vibrations, for instance, causecollisions of the particles for processing body fluid to generatemicroparticles. However, when blood is passed through a body fluidprocessor packed to a packing ratio in excess of 100%, the passage ofthe blood cells, particularly platelets, is unstable in many cases andthere also are cases in which the pressure drop increases progressivelyto ultimately prevent the blood to flow through the processor. This ispresumably because, in the case where the packing ratio exceeds 100%,the particles for processing body fluid are deformed and compressed ascompared with the pre-packing state and when the deformation andcompression are excessive, the clearances between particles are narrowedto adversely affect the efficiency of passage of the blood cells.

In contrast, in the case where the packing ratio is not higher than100%, passage of the blood cell is efficient and the blood can be passedunder the condition of stable pressure drop when blood flows. There isno particular lower limit of packing ratio but if the packing ratio istoo low, the packing amount of the particles for processing body fluidis so low that the objective body fluid processing cannot be easilyaccomplished. Moreover, if the packing ratio is decreased, the bloodprocessing efficiency is relatively sacrificed despite an increasedamount of blood withdrawn from the body. Therefore, the packing ratio ispreferably not less than 70%, more preferably not less than 85%, stillmore preferably not less than 90%, most preferably not less than 95%.

Further detailed analysis revealed that provided that the occupancyratio is 95% through 100%, most preferably 98% through 100%, even whenthe packing ratio is less than 100%, that is to say when the particlesfor processing body fluid are not held stationary but are free to move,and for that matter, 100%, the number of microparticles in the bodyfluid processor after vibrations is remarkably low. Furthermore, whenphysiological saline instead of blood was passed and the microparticlesmigrating from the body fluid processor was counted, substantially nomicroparticles could be detected, indicating that a body fluid processorwith a drastically reduced risk of leakage of microparticles can beprovided.

The particles for processing body fluid to be used in the presentinvention are solid at atmospheric temperature and pressure andwater-insoluble.

The morphology of the particles for processing body fluid for use in theinvention is generally spherical, with the mean particle diameter beingpreferably not less than 80 μm. If the mean particle diameter is toosmall, the inter-particle clearances are so narrow that the passage ofthe blood cells is liable to be interfere with. There is no criticalupper limit of mean particle diameter but an increasing mean particlediameter results in a decreasing surface area of the particles forprocessing body fluid and, hence, a decreasing body fluid processingefficiency. Therefore, the mean particle diameter is preferably not morethan 500 μm. The more preferred range of mean particle diameter is 120μm to 300 μm.

Regarding the particle size distribution of the particles for processingbody fluid according to the invention, all particles may be uniform indiameter or particles varying in diameter may co-exist presenting theso-called distribution in particle diameter. However, if the particlesize distribution is too broad, it may mean that many small particlesare present although the mean particle diameter is constant so that theinter-particle clearances are locally narrowed to obstruct passage ofthe blood cells. Therefore, the particle size distribution is preferablyas narrow as possible. More preferably, 50% or more of particles havediameters within ±20% of the mean diameter and still more preferably 60%or more of particles have diameters within ±20% of the mean diameter.

With regard to the strength of the particles for processing body fluidfor use in the invention, particles which are too soft or easilycollapsible are undesirable. The compaction resulting from bloodperfusion would make it impossible to secure a sufficient blood flowrate and, therefore, prolong the treatment time or even preventcontinuation of the treatment. To prevent this compaction of theparticles for processing body fluid, it is desirable to employ theparticles for processing body fluid having sufficiently high mechanicalstrength (hardness). The hardness referred to above means that when acylindrical column is uniformly packed with the particles for processingbody fluid and an aqueous fluid is admitted into the column, therelation of pressure drop and flow rate is linear at least until thepressure drop has reached 0.3 kgf/cm² (ca 220 mmHg) as will be explainedhereinafter in reference examples.

The particles for processing body fluid for use in the inventionpreferably has a porous structure having a multiplicity of pores ofadequate size in consideration of the efficiency of body fluidtreatment. The porous structure mentioned above is not only relevant toa solid substance having micropores defined by clusters of microspheresas occurring when a fundamental polymer carrier forms a single sphericalparticle due to cohesion of microspheres but also relevant to a solidsubstance having micropores formed by and among clusters of nucleiwithin the individual microspheres constituting a fundamental polymercarrier or the micropores which form when a copolymer having athree-dimensional structure (a polymer network) is swollen by an organicsolvent which has an affinity for the copolymer.

The constituent material of the carrier for the particles for processingbody fluid according to the invention is not particularly restricted butincludes such representative materials as organic carriers composed ofpolysaccharides such as cellulose and its derivatives, dextrin and soforth and synthetic polymers such as polystyrene, polyacrylamide,polyacrylate esters, polymethacrylate esters, polyvinyl alcohol,saponified poly(ethylene-co-vinyl acetate) and so forth. Moreover, forsuppressing the formation of microparticles and facilitating the passageof the blood cells, the surface of the particles for processing bodyfluid is preferably as smooth as possible.

Among the carrier materials mentioned above, hydrophilic carriers arepreferred because non-specific adsorption is small. The term‘hydrophilic carrier’ is used in this specification to mean a carriersuch that when the compound constituting it is formed into a flat board,its angle of contact with water is not larger than 60 degrees. Suchcarriers typically include cellulose and its derivatives, poly(vinylalcohol), saponified poly(ethylene-co-vinyl acetate), and polyacrylamidecarriers, although these are not exclusive choices.

Among these, cellulosic carriers are most advantageous. Cellulosiccarriers have many meritorious characteristics such as (1) comparativelyhigh mechanical strength and toughness with a minimum risk of thecollapse and the generation of microparticles, and high resistance tocompaction in a column even under the high-rate flow of blood, thusallowing blood to be passed at a high flow rate and (2) high safety ascompared with synthetic polymer carriers. Thus, these carriers can beused with the greatest advantage for the particles for processing bodyfluid according to the invention.

In the context of the present invention, the term “cellulosic” is usedreferring to at least one of natural cellulose, regenerated cellulose,and cellulose derivatives. Natural cellulose, for instance, includesdefatted cotton fiber, linen, pulp made by removing lignin,hemicellulose and so forth from wood, and purified cellulose obtainableby further purification of said pulp, among others. Regeneratedcellulose is a cellulose obtained by derivatizing natural cellulose intoa cellulose derivative and regenerating it by, for example, hydrolysis.The cellulose derivative includes derivatives of natural or regeneratedcellulose as obtained by partial or total esterification and/oretherification of its hydroxyl groups, among others. Specifically, thederivative of a cellulose obtained by partial or total esterification ofits hydroxyl groups includes but is not limited to cellulose acetate,cellulose propionate, cellulose butyrate, nitrocellulose, cellulosesulfate, cellulose phosphate, cellulose acetate butyrate, cellulosenitrate, and dicarboxlic esters of cellulose. The cellulose derivativeobtained by partial or total etherification of its hydroxyl groupsincludes but is not limited to methylcellulose, ethylcellulose,benzylcellulose, cyanoethylcellulose, carboxymethylcellulose,aminoethylcellulose, and hydroxyethylcellulose.

While any of these carriers may be used, as it is, as the particles forprocessing body fluid, any of such carriers may be conjugated orotherwise coupled with the so-called ligand and used as the particlesfor processing body fluid. The ligand that can be immobilized includesbut is not limited to amino acids such as phenylalanine, tryptophan,etc., polylysine, diethylaminoethyl-compounds and other positivelycharged compounds, polyacrylic acid, dextran sulfate and othernegatively charged compounds, n-hexadecylamine and other hydrophobiccompounds, polymyxin and other antibiotics, antibodies againstaccumulated disease-related factors or partial peptides of suchantibodies.

The filling liquid for use in the invention includes water, electrolytesolutions (physiological saline, sodium citrate solution, etc.), buffersolutions for maintaining pH constant (citric acid-sodium citratebuffer, citric acid-sodium hydroxide buffer, citric acid-disodiumhydrogenphosphate buffer, phosphate buffer, etc.), antioxidant solutionsfor preventing degradation of the particles for processing body fluid(sodium sulfite-containing aqueous solution, sodiumpyrosulfite-containing aqueous solution, L-ascorbic acid-containingaqueous solution, DL-α-tocopherol-containing aqueous solution, etc.)among others, and these can be selectively used according tocharacteristics of the particles for processing body fluid.

The capacity of the body fluid processor and the flow rate of blood,among other variables, can be judiciously selected depending on thetherapeutic goal and the patient's condition. Generally speaking, thecapacity of the body fluid processor may be 100 to 1000 ml and the flowrate of blood to be treated is not more than 200 ml/min. In cases wherethe patient's body weight is heavy and/or the concentration of thedisease-related factor to be depressed is high, the absolute amount ofthe disease-related factor whose level is to be depressed is so largethat the body fluid processor is also required to have a large capacity.An extracorporeal circulation treatment may be performed using a bodyfluid processor of large capacity, of course, but for the purpose oflessening the burden on the patient, for instance, it may be areasonable approach to somewhat reduce the concentration of thedisease-related factor using a body fluid processor, then either replacethe used processor with an unused one or regenerate the used one torestore its potency to reduce the concentration of the disease-relatedfactor, and perform an additional session of extracorporeal circulationtreatment.

The anticoagulant which can be used in such an extracorporealcirculation treatment with the body fluid processor according to theinvention includes heparin, low-molecular-weight heparin, nafamostatmesylate, gabexate mesylate, argatroban, citric acid-containinganticoagulants such as acid-citrate-dextrose (ACD) solution andcitrate-phosphate-dextrose (CPD) solution, and any of these can beemployed. Above all else, citric acid-containing anticoagulants, namelyACD-A solution and CPD-A solution, are used as advantageousanticoagulants because these agents chelate the calcium ions in blood toexhibit strong anticoagulant actions.

An example of the extracorporeal circulation system using the body fluidprocessor of the invention is now described. A blood collecting circuitfor guiding the blood drawn from the patient's body to the body fluidprocessor is connected to the fluid inlet of the processor, while ablood return circuit for returning the blood cleared of the causativefactor by adsorption to the patient's body is connected to the fluidoutlet of the processor. Then, a pump is set for delivery of the bloodto the blood collecting circuit. Moreover, an air chamber is connectedto a manometer to measure the fluid inlet pressure and fluid outletpressure of the body fluid processor, whereby the pressure drop of thebody fluid processor can be determined. In practical treatment, theblood withdrawn from the patient's body is treated with a suitableanticoagulant and delivered to the body fluid processor in which theconcentration of the disease-related factor is lowered and the blood sotreated is returned to the patient's body.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic cross-section view showing an example of the bodyfluid processor according to the invention.

FIG. 2 is a graph showing the relation between flow rate and pressuredrop as found when a cylindrical column is uniformly packed with thenecessary materials and water is passed through the column.

The body fluid processor of the invention is now described in detailreferring to FIG. 1 which shows an example of the processor in schematiccross-section. In FIG. 1, the reference numeral 1 indicates a body fluidinlet, 2 a body fluid outlet, 3 the particles for processing body fluid,4 a filling liquid, 5 and 6 each a mesh, 7 a column, and 8 a body fluidprocessor. It should, however, be understood that the body fluidprocessor according to the invention is not limited to the abovespecific embodiment but may virtually be any processor comprising avessel equipped with a fluid inlet, a fluid outlet, and meshes forpreventing the particles for processing body fluid from leaking out fromthe vessel packed with the particles for processing body fluid.

BEST MODES FOR CARRYING OUT THE INVENTION

The method of the invention is now specifically described by way ofexamples but is by no means restricted to these specific examples.

REFERENCE EXAMPLE

A glass cylindrical column (9 mm in. dia., 150 mm long) fitted with afilter (15 μm aperture dia.) at either end was uniformly packed with anagarose material (product of Bio-rad, Biogel A-5m, particle size: 50 to100 mesh), a polyvinyl resin material (product of Tosoh Corporation,Toyopearl HW-65, particle size: 50 to 100 μm), and a cellulosic material(product of Chisso Corporation, Cellulofine GC-700 m, particle size: 45to 105 μm). Then, water was admitted into the column with a peristalticpump to determine the relation between flow rate and pressure drop ΔP.The results are shown in FIG. 2.

It can be seen from FIG. 2 that whereas the flow rate increasedgenerally in proportion with the increase in pressure drop in the caseof Toyopearl HW-65 and Cellulofine GC-700m, Biogel A-5m was compacted sothat the flow rate failed to increase even when the pressure drop wasincreased. In the present invention, any material showing a linearrelation between pressure drop ΔP and flow rate at least until thepressure drop has reached 0.3 kgf/cm² (ca 220 mmHg), as it is true ofthe former materials, is regarded as being hard.

Example 1

To 2000 ml of porous cellulose beads with a mean particle diameter ofabout 190 μm (product of Chisso Corporation) were added 2000 ml ofwater, 1060 ml of 2 N aqueous solution of NaOH, and 360 ml ofchloromethyloxysilane, and the mixture was stirred at 40° C. for 2hours. After completion of the reaction, the beads were rinsedthoroughly with water to give epoxy-activated cellulose beads.

In 630 ml of water was dissolved 930 g of dextran sulfate (product ofMeito Sangyo Co., sulfur content ca 18%) to prepare an aqueous solutionof dextran sulfate and 2000 ml of the epoxy-activated cellulose beadsand 100 ml of water were added to the solution. After the mixture wasadjusted to pH 9.5 with an aqueous solution of NaOH, the reaction wascarried out at 45° C. for 22 hours. After this reaction, the beads werethoroughly washed with water and aqueous solution of NaCl and followingaddition of 19.6 ml of 2-aminoethanol, the mixture was allowed to standat 45° C. for 2 hours to block the unreacted epoxy groups. Thereafter,the beads were thoroughly rinsed with water to give dextransulfate-immobilized cellulose beads (the particles for processing bodyfluid).

Of the above the particles for processing body fluid, 138 ml insedimentation volume was taken and packed into a 3.1 cm (in. dia.)cylindrical vessel (the volume of packed zone: ca 142 ml) equipped withtwo 50 μm-apertured polyester meshes rigidly mounted at a mesh-to-meshdistance of 18.8 cm to prepare a body fluid processor with a packingratio of ca 97% and an occupancy ratio of ca 100%. Physiological salinewas used as a filling liquid.

Using 1200 ml of bovine blood (ionized Ca concentration: ca 0.45 mM),which has been subjected to anticoagulation by citric acid, as a bloodpool, the blood was circulated through the above body fluid processor ata flow rate of 20 ml/min (superficial linear velocity: ca 2.6 cm/min)(the time of circulation start was designated as min-O). As a result, astabilized passage of the blood cell was obtained over min-O to min-90.During this time the pressure drop of the body fluid processor wasstable around 70 mmHg. During the subsequent period of min-90 to min-95,increasing the flow rate to 29 ml/min (superficial linear velocity: ca3.9 cm/min) resulted in a stable blood perfusion with the pressure dropof the body fluid processor being stable around 110 mmHg. During theperiod of min-95 to min-100, increasing the flow rate to 39 ml/min(superficial linear velocity: ca 5.2 cm/min) resulted in a stable bloodperfusion with the pressure drop of the body fluid processor beingstable around 160 mmHg. Then, during min-100 to min-105, increasing theflow rate to 49 ml/min (superficial linear velocity: ca 6.5 cm/min)resulted in a stable blood perfusion with the pressure drop of the bodyfluid processor being stable around 210 mmHg. The passage ratio of bloodcells was also satisfactory. The passage ratios of various blood cellswere shown in Table 1.

The passage ratios of various blood cells were determined by samplingthe blood serially at the inlet and outlet of the body fluid processor,counting the cells with a blood cell counter (manufactured by SysmexCorporation, K-4500), and calculating the ratio by means of thefollowing equation.Passage ratio of blood cells=the number of blood cells at fluid outletof the body fluid processor/the number of blood cells at fluid inlet ofthe body fluid processor

Example 2

Of the particles for processing body fluid prepared in Example 1, 142 mlin sedimentation volume was taken and packed into a vessel similar tothe one used in Example 1 to prepare a body fluid processor with apacking ratio of ca 100% and an occupancy ratio of ca 100%.Physiological saline was used as a filling liquid.

Using 1200 ml of bovine blood (ionized Ca concentration: ca 0.6 mM),which has been subjected to anticoagulation by citric acid, as a bloodpool, the blood was circulated through the body fluid processor at aflow rate of 20 ml/min (superficial linear velocity: ca 2.6 cm/min) (thetime of circulation start was designated as min-0). As a result, astabilized passage of the blood cell was obtained over min-O to min-90.During this time the pressure drop of the body fluid processor wasstable around 90 mmHg. During the subsequent period of min-90 to min-95,increasing the flow rate to 29 ml/min (superficial linear velocity: ca3.9 cm/min) resulted in a stable blood perfusion with the pressure dropof the body fluid processor being stable around 130 mmHg. During theperiod of min-95 to min-100, increasing the flow rate to 39 ml/min(superficial linear velocity: ca 5.2 cm/min) resulted in a stable bloodperfusion with the pressure drop of the body fluid processor beingstable around 190 mmHg. Furthermore, during the period of min-100 tomin-105, increasing the flow rate to 49 ml/min (superficial linearvelocity: ca 6.5 cm/min) resulted in a stable blood perfusion with thepressure drop of the body fluid processor being stable around 250 mmHg.The passage ratio of blood cells was also satisfactory. The passageratios of various blood cells were shown in Table 1.

Example 3

Of the particles for processing body fluid prepared in Example 1, 708 mlin sedimentation volume was taken and packed into a 7.0 cm (in. dia.)cylindrical vessel (the volume of packed zone: ca 730 ml) equipped withtwo 48 μm-apertured polyester meshes rigidly mounted at a mesh-to-meshdistance of 19 cm to prepare a body fluid processor with a packing ratioof ca 97% and an occupancy ratio of ca 100%. Citric acid-sodium citratebuffer (pH=6.0) was used as a filling liquid.

The body fluid processor was washed with 2000 ml of physiological salineand using 7000 ml of bovine blood (ionized Ca concentration: ca 0.5 mM),which has been subjected to anticoagulation by citric acid, as a bloodpool, the blood was circulated through the body fluid processor at aflow rate of 100 ml/min (superficial linear velocity: ca 2.6 cm/min)(the time of circulation start was designated as min-0). As a result, astabilized passage of the blood cell was obtained over min-O to min-90.During this time the pressure drop of the body fluid processor wasstable around 70 mmHg. During the subsequent period of min-90 to min-95,increasing the flow rate to 150 ml/min (superficial linear velocity: ca3.9 cm/min) resulted in a stable blood perfusion with the pressure dropof the body fluid processor being around 110 mmHg. During the period ofmin-95 to min-100, increasing the flow rate to 200 ml/min (superficiallinear velocity: ca 5.2 cm/min) resulted in a stable blood perfusionwith the pressure drop of the body fluid processor being stable around160 mmHg. The passage ratio of blood cells was also satisfactory. Thepassage ratios of various blood cells were shown in Table 1.

Comparative Example 1

Of the particles for processing body fluid prepared in Example 1, 146 mlin sedimentation volume was taken and packed into a vessel similar tothe one used in Example 1 to prepare a body fluid processor with apacking ratio of ca 103% and an occupancy ratio of more than 100%.Physiological saline was used as a filling liquid.

Using 1200 ml of bovine blood (ionized Ca concentration: ca 0.6 mM),which has been subjected to anticoagulation by citric acid, as a bloodpool, the blood was circulated through the body fluid processor at aflow rate of 20 ml/min (superficial linear velocity: ca 2.6 cm/min). Asa result, a stabilized passage of the blood cell was achieved with apressure drop of ca 90 mmHg up to around min-75 but subsequently agradual gain in pressure drop was noted, with the pressure drop being ashigh as ca 120 mmHg at min-90. The passage ratio of blood cells declinedwith time. The passage ratios of various blood cells were shown in Table1.

Comparative Example 2

Using porous cellulose beads with a mean particle diameter of ca 210 μm,the procedure described in Example 1 was otherwise repeated to givedextran sulfate-immobilized cellulose beads (the particles forprocessing body fluid). Of the particles for processing body fluid, 781ml in sedimentation volume was taken and packed into a vessel similar tothe one used in Example 3 to prepare a body fluid processor with apacking ratio of ca 107% and an occupancy ratio of more than 100%.Physiological saline was used as a filling liquid.

Using 7000 ml of bovine blood (ionized Ca concentration: ca 0.45 mM),which has been subjected to anticoagulation by citric acid, as a bloodpool just as in Example 3, the blood was circulated through the bodyfluid processor at a flow rate of 100 ml/min (superficial linearvelocity: ca 2.6 cm/min). The blood could be passed in a stable mannerwith the pressure drop being stable around 100 mmHg during an initialphase of treatment but the pressure drop increased sharply about 30minutes after the start of circulation. After about 40 minutes, thepressure drop reached about 350 mmHg due to compaction of the particlesfor processing body fluid, preventing circulation of blood. The passageratio of blood cells, especially the passage ratio of platelets, wasextremely low. The passage ratios of various blood cells were shown inTable 1.

Example 4

Of the particles for processing body fluid prepared in Example 1, 13.4ml in sedimentation volume was taken and packed into a 1 cm (in. dia.)cylindrical vessel (the volume of packed zone: ca 14.9 ml) equipped withtwo 50 μm-apertured polyester meshes rigidly mounted at a mesh-to-meshdistance of 19 cm to prepare a body fluid processor with a packing ratioof ca 90% and an occupancy ratio of ca 100%. Citric acid-sodium citratebuffer (pH=6.0) was used as a filling liquid.

This body fluid processor was washed with 2000 ml of physiologicalsaline and using 60 ml of bovine blood (ionized Ca concentration: ca 0.2mM), which has been subjected to anticoagulation by citric acid, as ablood pool, the blood was circulated through the above body fluidprocessor at a flow rate of 0.6 ml/min (superficial linear velocity: ca0.76 cm/min) during the initial 15-minute period and, thereafter, at aflow rate of 1.6 ml/min (superficial liner velocity: ca 2.0 cm/min). Asa result, passage of the blood cell was satisfactory and a stable bloodcirculation could be obtained. The passage ratios of various blood cellswere shown in Table 1.

Comparative Example 3

Of the particles for processing body fluid prepared in Example 1, 15.5ml, 16.4 ml, and 17.9 ml, all in sedimentation volume, were taken andpacked into vessels similar to those used in Example 4 to prepare bodyfluid processors with packing ratios of ca 104%, ca 110% and ca 120%,respectively, and a uniform occupancy ratio of more than 100%.Physiological saline was used as a filling liquid.

Bovine blood was circulated through these body fluid processors in thesame manner as in Example 4. As a result, passage of the platelet wasinvariably unstable and column plugging took place, preventingcontinuation of circulation after 60 minutes. The passage ratios ofvarious blood cells were shown in Table 1.

Example 5

Of the particles for processing body fluid prepared in Example 1, 11.9ml in sedimentation volume was taken and packed into a 1 cm (in. dia.)cylindrical vessel (the volume of packed zone: ca 12.7 ml) equipped withtwo 50 μm-apertured polyester meshes rigidly mounted at a mesh-to-meshdistance of 16.2 cm to prepare a body fluid processor with a packingratio of ca 94% and an occupancy ratio of ca 100%. Physiological salinewas used as a filling liquid.

Through this body fluid processor, human blood treated with 10 volume %to the blood of the anticoagulant ACD-A solution was passed at a flowrate of 1.2 ml/min (superficial linear velocity: ca 1.5 cm/min) in aone-pass mode. As a result, passage of the blood cell was satisfactoryand a stable blood perfusion could be obtained. The passage ratios ofvarious blood cells were shown in Table 1.

Comparative Example 4

Of the particles for processing body fluid prepared in Example 1, 14.0ml and 15.2 ml, both in sedimentation volume, were respectively takenand packed into a vessel similar to the one used in Example 5 to preparebody fluid processors with packing ratios of ca 110% and ca 126%,respectively, and a uniform occupancy ratio of more than 100%.Physiological saline was used as a filling liquid.

When human blood was passed in the same manner as in Example 5, passageof the platelet was unstable, preventing circulation of blood in about30 minutes with both processors. The passage ratios of various bloodcells were shown in Table 1.

Example 6

Except that porous cellulose beads with a mean particle diameter ofabout 270 μm were used in lieu of the porous cellulose beads with a meanparticle diameter of 190 μm, the procedure described in Example 1 wasrepeated to prepare the particles for processing body fluid.

Of the above particles for processing body fluid, 13.9 ml insedimentation volume was taken and packed into a vessel similar to theone used in Example 4 to prepare a body fluid processor with a packingratio of ca 93% and an occupancy ratio of ca 100%. Physiological salinewas used as a filling liquid.

Using 70 ml of human blood treated with 10 volume % to the blood of theanticoagulant ACD-A solution as a blood pool, the blood was circulatedthrough the above body fluid processor at a flow rate of 0.6 ml/min(superficial linear velocity: ca 0.76 cm/min) during the initial 15-minperiod and a flow rate of 1.6 ml/min (superficial linear velocity: ca2.0 cm/min) thereafter. As a result, passage of the blood cell wassatisfactory and a stable blood perfusion could be obtained. The passageratios of various blood cells were shown in Table 1.

Furthermore, this body fluid processor was found to efficiently adsorblow-density lipoprotein-cholesterol (LDL-C) and triglyceride (TG).

Before blood perfusion After blood perfusion LDL-C concentration ofblood pool 88 20 (mg/dl-plasma) TG concentration of blood pool 110 57(mg/dl-plasma)

TABLE 1 Conditions of Packing Occupancy Passage ratio of blood cells [%]blood perfusion ratio [%] ratio [%] 30 minutes 60 minutes 90 minutesExample 1 Bovine blood/ 97 100 Erythrocyte 97 101 101 circulationLeukocyte 96 89 86 Platelet 86 87 86 Example 2 Bovine blood/ 100 100Erythrocyte 104 98 98 circulation Leukocyte 98 93 91 Platelet 89 117 93Example 3 Bovine blood/ 97 100 Erythrocyte 112 92 100 circulationLeukocyte 101 80 80 Platelet 110 93 107 Example 4 Bovine blood/ 90 100Erythrocyte 108 91 89 circulation Leukocyte 102 99 101 Platelet 112 10294 Example 5 Human blood/ 94 100 Erythrocyte 100 Not performed Notperformed one-pass Leukocyte 100 Not performed Not performed Platelet 97Not performed Not performed Example 6 Human blood/ 93 100 Erythrocyte100 100 100 circulation Leukocyte 99 99 100 Platelet 99 94 101Comparative Bovine blood/ 103 more than Erythrocyte 101 97 93 Example 1circulation 100 Leukocyte 95 86 68 Platelet 58 61 2 Comparative Bovineblood/ 107 more than Erythrocyte 98 Passage infeasible Passageinfeasible Example 2 circulation 100 Leukocyte 67 Passage infeasiblePassage infeasible Platelet 11 Passage infeasible Passage infeasibleComparative Bovine blood/ 104 more than Erythrocyte 76 Passageinfeasible Passage infeasible Example 3-1 circulation 100 Leukocyte 99Passage infeasible Passage infeasible Platelet 12 Passage infeasiblePassage infeasible 3-2 Bovine blood/ 110 more than Erythrocyte 75 58Passage infeasible circulation 100 Leukocyte 99 89 Passage infeasiblePlatelet 43 26 Passage infeasible 3-3 Bovine blood/ 120 more thanErythrocyte 81 Passage infeasible Passage infeasible circulation 100Leukocyte 95 Passage infeasible Passage infeasible Platelet 19 Passageinfeasible Passage infeasible Comparative Human blood/ 110 more thanErythrocyte 96 Not performed Not performed Example 4-1 one-pass 100Leukocyte 100 Not performed Not performed Platelet 9 Not performed Notperformed 4-2 Human blood/ 126 more than Erythrocyte 97 Not performedNot performed one-pass 100 Leukocyte 100 Not performed Not performedPlatelet 36 Not performed Not performed

Example 7

Of the particles for processing body fluid prepared in Example 1, 640 mland 654 ml, both in sedimentation volume, were taken and packed intovessels similar to those used in Example 3 to prepare two body fluidprocessors with packing ratios of ca 88% and ca 90%, respectively, and auniform occupancy ratio of ca 100%. Citric acid-sodium citrate buffersolution (pH=6.0) was used as a filling liquid.

Each of these body fluid processors was packaged with a suitablecushioning material, accommodated in a box, and as a simulation ofcommercial shipment and storage, vibrated in horizontal and verticaldirections for 1 hour each in accordance with JIS Z0232 “Methods forVibration Test of Packaged Articles for Transportation and Containers”.From the body fluid processor after vibration, the particles forprocessing body fluid were flushed out with a microparticle-free liquidto withdraw the entirety of the particles together with the fillingliquid in the slurry form into a recovery vessel. This slurry was shakento separate the microparticles from the particles for processing bodyfluid and allowed to stand for 3 minutes. Then, 2 ml of the supernatantwas taken and analyzed for the concentration of the microparticles inthe supernatant. This microparticle concentration was multiplied by thevolume of the liquid phase of the slurry to find the number ofmicroparticles in the body fluid processor. As a result, the number ofmicroparticles measuring not less than 10 μm but less than about 50 μmin diameter was 4904 on the average and the number of microparticlesmeasuring not less than 25 μm but less than about 50 μm in diameter was455 on the average. For determination of the concentration ofmicroparticles, a Coulter Counter of the electric resistance type wasused and as the aperture tube, a 100 μm tube was used.

Example 8

Of the particles for processing body fluid prepared in Example 1, 655 mlin sedimentation volume was taken and packed into a vessel similar tothe one used in Example 3 to prepare a body fluid processor with apacking ratio of ca 90% and an occupancy ratio of ca 100%. Citricacid-sodium citrate buffer solution (pH=6.0) was used as a fillingliquid.

This body fluid processor was vibrated in the same manner as in Example7. Using the body fluid processor after vibration, the number ofmicroparticles flushed out of the body fluid processor was counted bythe following method taking the practical setting into consideration.

Physiological saline for injection was delivered into the body fluidprocessor at a flow rate of 100 ml/min (superficial linear velocity: ca2.6 cm/min) for 2 hours and test fluid samples flowing out of the bodyfluid processor were collected immediately after passage and at 0.5 hr,1 hr, 1.5 hr, and 2 hr. In parallel, physiological saline for injectionwas sampled as a blank test. Using a Coulter counter, the number ofmicroparticles in each of the test samples and blank test samples wascounted and the difference in the number of microparticles between thetest sample and the blank test sample was taken as the number ofgenerated microparticles. Determination of the number of themicroparticles from the body fluid processor revealed no microparticles.

Example 9

A commercial cellulose acetate was dissolved in a solvent mixture ofdimethyl sulfoxide and propylene glycol and this solution was made intodroplets and coagulated by the method described in Japanese KokaiPublication Sho-63-117039 (vibration method) to prepare celluloseacetate beads. The beads were mixed with an aqueous solution of sodiumhydroxide for hydrolysis to give cellulose beads. The mean particlediameter of the cellulose beads was 460 μm.

After a sufficient quantity of water was added to 1700 ml of theepoxy-activated cellulose beads to make 3400 ml, 900 ml of 2 M aqueoussodium hydroxide solution was added and the temperature was adjusted to40° C. To this mixture was added 310 ml of chloromethyloxysilane, andthe reaction was carried out under stirring at 40° C. for 2 hours. Aftercompletion of the reaction, the beads were thoroughly rinsed with waterto give epoxy-activated cellulose beads.

To 1000 ml of the above epoxy-activated cellulose beads was added 20 gof n-hexadecylamine, and the reaction was conducted in 50 (v/v) %ethanol/water under standing at 45° C. for 6 days. After completion ofthe reaction, the beads were serially washed well with 50 (v/v) %ethanol/water, ethanol, 50 (v/v) % ethanol/water, and water to given-hexadecylamine-coupled cellulose beads (the particles for processingbody fluid).

Of the above the particles for processing body fluid, 300 ml and 330 ml,both in sedimentation volume, were respectively taken and packed into7.0 cm (in. dia.) cylindrical vessels (the volume of packed zone: ca 350ml) each equipped with two 150 μm-apertured polyester meshes rigidlymounted at a mesh-to-mesh distance of 9.1 cm to prepare body fluidprocessors with packing ratios of ca 86% and ca 94%, respectively, and auniform occupancy ratio of ca 98.9%. Citric acid-sodium citrate buffer(pH=6.0) was used as a filling liquid.

These body fluid processors were vibrated in the same manner as inExample 7 and the number of microparticles in each body fluid processorwas determined. As a result, the number of microparticles measuring notless than 10 μm but less than about 50 μm in diameter was 4851 on theaverage and the number of microparticles measuring not less than 25 μmbut less than about 50 μm in diameter was 139 on the average.

Comparative Example 5

Of the body fluid particles prepared in Example 9, 300 ml and 335 ml,both in sedimentation volume, were respectively taken and packed intovessels similar to those used in Example 9 to prepare body fluidprocessors with packing ratios of ca 87% and ca 94%, respectively, and auniform occupancy ratio of ca 94%. Citric acid-sodium citrate buffersolution (pH=6.0) was used as a filling liquid.

These body fluid processors were vibrated in the same manner as inExample 7 and the number of microparticles in each body fluid processorwas determined. As a result, the number of microparticles measuring notless than 10 μm but less than about 50 μm in diameter was 40589 on theaverage and the number of microparticles measuring not less than 25 μmbut less than about 50 μm in diameter was 2622 on the average.

Example 10

Except that porous cellulose beads with a mean particle diameter of ca240 μm was used in lieu of the porous cellulose beads with a meanparticle diameter of ca 190 μm, the procedure described in Example 1 wasrepeated to prepare the particles for processing body fluid.

Of the above the particles for processing body fluid, 708 ml insedimentation volume was taken and packed into a 7 cm (in. dia.)cylindrical vessel equipped with two 48 μm-apertured polyester meshesrigidly mounted at a mesh-to-mesh distance of 19.8 cm (the volume ofpacked zone: ca 760 ml) to prepare a body fluid processor with a packingratio of ca 93% and an occupancy ratio of ca 98%. Citric acid-sodiumcitrate buffer solution (pH=6.0) was used as a filling liquid.

This body fluid processor was vibrated and the number of microparticlesin the body fluid processor was counted in the same manner as in Example7. As a result, the number of microparticles measuring not less than 10μm but less than ca 50 μm in diameter was 6638 on the average and thenumber of microparticles measuring not less than 25 μm but less than ca50 μm was 1021 on the average.

INDUSTRIAL APPLICABILITY

In accordance with the present invention there can be provided a safeand practically useful body fluid processor enabling directhemoperfusion with a favorable passage of the blood cell and showing anextremely low risks of the generation and leakage of microparticles.Furthermore, as a body fluid processor enabling direct hemoperfusion isthus provided, the burden on the patient and medical staff can bereduced through, for example, a curtailed treatment session time.

1. A body fluid processor enabling direct hemoperfusion, which comprisesa vessel equipped with a fluid inlet, a fluid outlet and a mesh attachedadjacent to said fluid outlet, said vessel being packed with particlesfor processing body fluid and a filling liquid, and said body fluidprocessor having a packing ratio of 85 to 100% and the space in whichthe particles for processing body fluid are to be packed in the bodyfluid processor being filled with the particles for processing bodyfluid and said filling liquid at a ratio of 95% or more but not morethan 100%, wherein said packing ratio is a value calculated by means ofthe following equation:Packing ratio (%)=Va/Vj×100 where Va represents a sedimentation volumeof the particles for processing body fluid packed in the space in whichthe particles for processing body fluid are to be packed and Vjrepresents the volume of the space in which the particles for processingbody fluid are to be packed, and wherein the mean particle diameter ofthe particles for processing body fluid is 80 μm through 500 μm and theaperture size of the mesh is not less than 20 μm but less than ½ of themean particle diameter of the particles for processing body fluid. 2.The body fluid processor enabling direct hemoperfusion according toclaim 1, wherein the particles for processing body fluid are hardparticles.
 3. The body fluid processor enabling direct hemoperfusionaccording to claim 1, wherein a carrier for the particles for processingbody fluid is a hydrophilic carrier.
 4. The body fluid processorenabling direct hemoperfusion according to claim 1, wherein a carrierfor the particles for processing body fluid is a carrier made of acellulosic material.